Search

The local sensitivity of MRI can be improved with small MR detectors placed close to regions of interest. However, to maintain such sensitivity advantage, local detectors normally need to communicate with the external amplifier through cable connections, which prevent the use of local detectors as implantable devices. Recently, an integrated wireless amplifier was developed that can efficiently amplify and broadcast locally detected signals, so that the local sensitivity was enhanced without the need for cable connections. This integrated detector enabled the live imaging of individual glomeruli using negative contrast introduced by cation-ized ferritin, and the live imaging of renal tubules using positive contrast introduced by gadopentetate dimeglumine. Here, we utilized the high blood flow to image individual glomeruli as hyperintense regions without any contrast agent. These hyperintense regions were identified for pixels with signal intensities higher than the local average. Addition of Mn2+ allowed the simultaneous detection of both glomeruli and renal tubules: Mn2+ was primarily reabsorbed by renal tubules, which would be distinguished from glomeruli due to higher enhancement in T1-weighted MRI. Dynamic studies of Mn2+ absorption confirmed the differential absorption affinity of glomeruli and renal tubules, potentially enabling the in vivo observation of nephron function. [ABSTRACT FROM AUTHOR]

Manganese-block copolymer complexes (MnBCs) that contain paramagnetic Mn ions complexed with ionic-nonionic poly(ethylene oxide-b-poly(methacrylate) have been developed for use as a T[sub 1]-weighted MRI contrast agent. By encasing Mn ions within ionized polymer matrices, r1 values could be increased by 250-350% in comparison with free Mn ions at relatively high fields of 4.7 to 11.7 T. MnBCs were further manipulated by treatment with NaOH to achieve more stable complexes (iMnBCs). iMnBCs delayed release of Mn2+ which could be accelerated by low pH, indeed by cellular uptake via endocytosis into acidic compartments. Both complexes exhibited good T[sub 1] contrast signal enhancement in the liver following intravenous infusion. The contrast was observed in the gallbladder due to the clearance of Mn ions from the liver to the biliary process. iMnBCs, notably, showed a delayed contrast enhancement profile in the gallbladder, which was interpreted to be due to degradation and excretion of Mn2+ ions into the gallbladder. Intracortical injection of iMnBCs into the rat brain also led to delayed neuronal transport to the thalamus. The delayed enhancement feature may have benefits for targeting MRI contrast to specific cells and surface receptors that are known to be internalized by endocytosis. [ABSTRACT FROM AUTHOR]

Anionic copolymers can enable intracellular delivery of cationic drugs which otherwise cannot cross cell membrane barriers. We tested the efficacy of gentamicin-loaded magnetite block ionomer complexes (MBICs) against intracellular Brucella melitensis. Anionic block copolymers were used to coat nanomagnetite through adsorption of a portion of anions on the particle surfaces, then the remaining anions were complexed with 30–32 weight percentage of gentamicin. The zeta potential changed from −39 to −13 mV after encapsulation of the drug with complementary charge. The gentamicin-loaded MBICs had intensity average hydrodynamic diameters of 62 nm, while the polymer-coated nanomagnetite particles without drug were 34 nm in size. No toxicity as measured by a MTS assay was observed upon incubation of the MBICs with J774A.1 murine macrophage-like cells. Confocal microscopic images showed that the MBICs were taken up by the macrophages and distributed in the cell cytoplasm and endosomal/lysosomal compartments. Upon treatment with gentamicin-loaded MBICs (3.5 Log 10), B. melitensis-infected macrophages showed significantly higher clearance of Brucella compared to the treatment with free g (0.9 Log 10). Compared to doxycycline alone, a combination of doxycycline and gentamicin (either free or encapsulated in MBICs) showed significantly higher clearance of B.melitensis from chronically infected mice. Histopathological examination of kidneys from the MBICs-treated mice revealed multifocal infiltration of macrophages containing intracytoplasmic iron (MBICs) in peri-renal adipose. Although MBICs showed similar efficacy as free gentamicin against Brucella in mice, our strategy presents an effective way to deliver higher loads of drugs intracellularly and ability to study the bio-distribution of drug carriers. [ABSTRACT FROM AUTHOR]

Magnetic block ionomer complexes (MBICs) containing acombinationof therapeutic and imaging agents are of great interest for deliveringdrugs and tracking their biodistribution with magnetic resonance imaging.With an aim to develop nanocarriers with high drug loadings that integratemagnetic nanoparticles into one system, we herein report antibiotic-ladenMBICs based on assembly of poly(ethylene oxide-b-acrylate)(PEO-b-PAA) ionomers with nanomagnetite and gentamicin.The polymer was bound to the magnetic nanoparticle surfaces via ligandadsorption of the PAA block, thereby creating a double corona structurewith a nonionic PEO shell and an ionic region rich in PAA. The portionof carboxylates that were not bound to the magnetite provided bindingsites for drug loading via ionic complexation. PEO was chosen as ablock copolymer segment to improve biocompatibility and aid in dispersionthrough interparticle steric repulsion. Intensity average diametersincreased from 34 to 62 nm upon adding the drug, suggesting that theparticles formed small clusters. Zeta potentials decreased from approximately−40 without gentamicin to approximately −10 mV withthe drug, indicating that the drug effectively localized the chargesin the MBIC cores. Approximately 35 wt % of the encapsulated gentamicinwas released under physiological conditions within 10 h, and thiswas followed by slower release of another 7% by 18 h. The solid magnetitecore serves as a multifunctional substrate for block ionomers to stablyadsorb, thus acting as a pseudo-crosslinking site in the complexesthat enhances their stability. Complexes between PEO-b-PAA and gentamicin without magnetite instantaneously dissociatein saline buffer. When the same copolymer was adsorbed onto magnetite,subsequent complexation with gentamicin resulted in stable complexesthat withstood media with physiological ionic strength. [ABSTRACT FROM AUTHOR]

Treatment and eradication of intracellular pathogens such as Brucella is difficult because infections are localized within phagocytic cells and most antibiotics, although highly active in vitro, do not actively pass through cellular membranes. Thus, an optimum strategy to treat these infections should address targeting of active drugs to the intracellular compartment where the bacteria replicate, and should prolong the release of the antibiotics so that the number of doses and associated toxicity can be reduced. We incorporated streptomycin and doxycycline into macromolecular nanoplexes with anionic homo- and block copolymers via cooperative electrostatic interactions among the cationic drugs and anionic polymers. The approach enabled simultaneous binding of both antibiotics into the nanoplexes, and their use resulted in an improvement in performance as compared with the free drugs. Administration of two doses of the nanoplexes significantly reduced the Brucella melitensis load in the spleens and livers of infected BALB/c mice. The nanoplexes were more effective than free drugs in the spleens (0.72-log and 0.51-log reductions, respectively) and in the livers (0.79-log and 0.42-log reductions, respectively) of the infected mice. Further research regarding the design of optimum nanoplex structures will be directed towards alterations in both the core and the shell properties to investigate the effects of the rates and pathways of entry into immune cells where the brucellae replicate. [ABSTRACT FROM AUTHOR]

Manganese-block copolymer complexes (MnBCs) that contain paramagnetic Mn ions complexed with ionic-nonionic poly(ethylene oxide-b-poly(methacrylate) have been developed for use as a T1-weighted MRI contrast agent. By encasing Mn ion within ionized polymer matrices, r1 values could be increased by 250-350 % in comparison with free Mn ion at relative high fields of 4.7 to 11.7 T. MnBCs were further manipulated by treatment with NaOH to achieve more stable complexes (iMnBCs). iMnBCs delayed release of Mn 2+ which could be accelerated by low pH, indeed by cellular uptake via endocytosis into acidic compartments. Both complexes exhibited good T1 contrast signal enhancement in liver following intravenous infusion. The contrast was observed in gallbladder due to the clearance of Mn ion from liver to biliary process. iMnBCs, notably, showed a delayed contrast enhancement profile in gallbladder, which was interpreted to be due to degradation and excretion of Mn 2+ ions into the gallbladder. Intracortical injection of iMnBCs into the rat brain also led to delayed neuronal transport to thalamus. The delayed enhancement feature may have benefits for targeting MRI contrast to specific cells and surface receptors that are known to be internalized by endocytosis.

Biocompatible magnetic nanoparticles show great promise for many biotechnological applications. This paper addresses the synthesis and characterization of magnetite nanoparticles coated with poly(ethylene oxide) (PEO) homopolymers and amphiphilic poly(propylene oxide-b-ethylene oxide) (PPO-b-PEO) copolymers that were anchored through ammonium ions. Predictions and experimental measurements of the colloidal properties of these nanoparticles in water and phosphate-buffered saline (PBS) as functions of the polymer block lengths and polymer loading are reported. The complexes were found to exist as primary particles at high polymer compositions, and most formed small clusters with equilibrium sizes as the polymer loading was reduced. Through implementation of a polymer brush model, the size distributions from dynamic light scattering (DLS) were compared to those from the model. For complexes that did not cluster, the experimental sizes matched the model well. For complexes that clustered, equilibrium diameters were predicted accurately through an empirical fit derived from DLS data and the half-life for doublet formation calculated using the modified Derjaguin-Landau-Verwey-Overbeek (DLVO) theory. Deviation from this empirical fit provided insight into possible additional interparticle hydrophobic interactions for select complexes for which the DLVO theory could not account. While the polymers remained bound to the nanoparticles in water, most of them desorbed slowly in PBS. Desorption was slowed significantly at high polymer chain densities and with hydrophobic PPO anchor blocks. By tailoring the PPO block length and the number of polymer chains on the surface, flocculation of the magnetite complexes in PBS was avoided. This allows for in vitro experiments where appreciable flocculation or sedimentation will not take place within the specified time scale requirements of an experiment.